Indoles Buchwald-Hartwig amination

The first examples utilising A-heterocyclic carbenes as ligands in the Buchwald-Hartwig amination involved the in situ formation of the catalyst from the corresponding imidazolium salt and a Pd(0) source. Nolan reported IPr-HCl/PdjCdbalj as a catalytic system for the amination of aryl chlorides in excellent yields, using different types of amines, anilines, and also imines or indoles [142,143] (Scheme 6.46). Hartwig showed later that in some cases the reactions could be performed at room temperature and without anhydrous conditions even for aryl chlorides [ 144]. This was later shown for the less challenging bromides and iodides [145,146]. 

A less direct strategy for indole synthesis (58) is the intramolecular Buchwald-Hartwig amination of an enamine 57 catalyzed by (DPPF)PdCl2.99 It is necessary to use the Z-enamine isomer 57 that was set by a Homer-Wadsworth-Emmons reaction. 

Indoles can be synthesized via a palladium-mediated intramolecular amination reaction of an appropriately substituted haloarene. This is a specific application of the Buchwald-Hartwig amination reaction that has found use in the synthesis of biologically active natural products. 

The Buchwald-Hartwig amination reaction has also been applied to the synthesis of A -arylhydrazones, which can then be transformed into indoles via the Fisher indole synthesis. Since this reaction sequence does not use a Buchwald-Hartwig amination reaction directly in the synthesis of indoles, it will not be a focus of this chapter. 

The Buchwald-Hartwig amination reaction can facilitate the synthesis of nitrogen-containing heterocycles. For instance, Buchwald demonstrated that the amination reaction could be used to prepare N-arylhydrazones from hydrazones and aryl halides. Acid-catalyzed condensation of the hydrazone with a ketone then yielded the desired indoles.Hartwig described a similar arylhydrazone formation with DPPF as a ligand and CS2CO3 as a base."... 

Buchwald quickly parlayed this transformation into a versatile indole synthesis via oxidation of intermediate indolines prepared using the above intramolecular Buchwald-Hartwig amination. Variations leading directly to indoles and related nitrogen-containing heterocycles quickly followed and are described below. 

Heterocycles related to indoles can also be prepared using the Buchwald-Hartwig amination strategy. For instance, indazole 15 can be prepared from hydrazine 14. Benzimidazole derivatives may also be prepared from the intramolecular guanidinylation of aryl bromides. And oxindoles can be prepared from the intramolecular amidation of aryl bromides. ... 

Novel tetracyclic and pentacyclic indole derivatives can be prepared from readily available gem-dibromovinyl substrates in a single step by means of an efQdent Pd-catalyzed domino Buchwald-Hartwig amination/direct arylation reaction. Enhanced reactivity and selectivity are obtained by the addition of silver salts (Bryan and Lautens 2008). 

With the development of Buchwald-Hartwig amination reactions, the amine component of these indoles can also be introduced into these precursors via palladium catalysis [8]. As shown by Ackermann, this can be coupled with aryl halide alkynylation and cyclization to provide a one-pot, three-component synthesis of substituted indoles (Scheme 6.6) [9]. In this case, simple ortho-dihaloarene derivatives S were employed as starting materials, with Sonogashira coupling occurring at the more activated aryl-iodide bond, followed by selective coupling of various alkyl or arylamines. Alternatively, Zhao has recently demonstrated that amination can be performed on both bromoalkyne 6, followed by the aryl-bromide bond, to provide a route to 2-amidoindoles (Scheme 6.7) [10]. 

Indole is one of the most important heterocyclic scaffolds for drug discovery. Approaches for indole synthesis using hydroamination as a key step in their syntheses has been an ongoing area of investigation over the past several years [329, 330]. Early examples focused on one-pot intermolecular hydrohydrazination followed by the Lewis-acid-catalyzed Fischer indole synthesis [331, 332] (Scheme 15.102) or one-pot intermolecular hydroamination followed by cross-coupling to either form a C-N bond (via the Buchwald-Hartwig amination) [333] (Scheme 15.103) or a C-C bond (via a Heck reaction) [334, 335] (Scheme 15.104). Alternatively, o-alkynylanilines can be used directly as substrates for intramolecular hydroamination (Scheme 15.105) [198, 200, 336-340]. These approaches have been thoroughly reviewed [10]. 

Buchwald parlayed the powerful Buchwald-Hartwig aryl amination technology [439-447] into a simple and versatile indoline synthesis [448-452], For example, indole 368, which has been employed in total syntheses of the marine alkaloids makaluvamine C and damirones A and B, was readily forged via the Pd-mediated cyclization shown below [448], This intramolecular amination is applicable to the synthesis of -substituted optically active indolines [450], and o-bromobenzylic bromides can be utilized in this methodology, as illustrated for the preparation of 369 [451]. Furthermore, this Pd-catalyzed amination reaction has been applied to the synthesis of arylhydrazones, which are substrates for the Fischer indole synthesis [453,454],... 

N-Aryl amination, or the Buchwald-Hartwig reaction, has proven to be a useful and versatile method to obtain aryl amines, which are of great synthetical and industrial interest [145]. The first examples of carbene/palladium-catalyzed amination of aryl halides showed that in situ-generated catalyst could efficiently mediate the coupling of aryl halides with primary and secondary amines, imines and indoles [ 146-148]. Even if most of these reactions could be carried out at room temperature with aryl iodides and bromides, elevated temperatures were required in order to couple aryl chlorides. 

Orr/zc- em-Dihalovinylanilines 278 were also used in another example of a Buchwald-Hartwig-type/Mizoroki-Heck reaction for the synthesis of 2-vinylic indoles 279 (Scheme 8.69). Lautens and coworkers [140] recently illustrated a domino coupUng under Jeffery s condition where the aniline nitrogen undergoes an amination step followed by a Mizoroki-Heck coupling with various alkenes. In this process, electronic factors and steric hindrance of the different substituents had only a small effect on the yield however, in the formation of 3-substituted indoles using this method only very poor yields were obtained. The procedure can also be performed in an intramolecular mode leading to tricycUc compounds such as pyridino and azepino indoles 281 and 282 (Scheme 8.69). 

Several tandem reaction sequences have been developed for indole synthesis featuring a Buchwald-Hartwig aryl amination as one component. For instance, a tandem double JV-arylation of substrate 5 leads to indoles 6 through a cascade of C-N bond forming reactions. A range of structurally and electronically diverse amines can be used successfully in this transformation. 

Indoles can also be prepared directly from o-chlorophenyl-2-alkyl alkynes and primary amines via a tandem alkyne hydroamination/Buchwald-Hartwig iV-arylation sequence, as illustrated for the conversion of 7 to 8 via intermediate enamine 9. ... 

Amines in Reactions Based on Buchwald Hartwig Aminativn A number of strategies of indole derivatives... 

Recently, Buchwald and Hartwig have developed the palladium-catalyzed coupling reaction of aryl halides with amines (Scheme 165), and they have extended this reaction to the intramolecular version to give a variety of the aza-heterocyclic compounds 547 (Scheme 166).231 This methodology has provided a wide variety of alkaloids, such as indoles,232 inda-zoles,233 benzimidazoles,234 benazepines,235 phena-zines,236 carbapenems,237 the mitomycin ring system,238 a-carbolines,239 and polyheterocycles.240 Pharmacologically active natural products, such as (—)-asperlicin (550) (Scheme 167),241 dehydrobufotenine (553) (Scheme 168),242 and makaluvamine C... 

The Hartwig-Buchwald arylation of amines can also be favorably combined with the Heck reaction [383, 384]. For example, the intramolecular palladium-catalyzed N-arylation of immobilized dehydro(halophenyl)alaninate was found to proceed smoothly to form indolecarboxylates. The method was successfully combined with the Heck reaction to constitute a one-pot indole synthesis in the form of a palladium-catalyzed cascade C,N-arylation reaction (Scheme 8.58) [383, 384]. 

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